Obesity is a condition characterized by an excess of body fat. The prevalence of overweight and obesity is considered an important public health issue in the world. Roughly two thirds of US adults meet the criteria for overweight or obesity. Actually, obesity is an important risk factor for coronary heart disease (CHD), ventricular dysfunction, congestive heart failure, stroke, and cardiac arrhythmias. Furthermore obesity is closely associated with type 2 diabetes, metabolic syndrome and hepatic disorders such as non-alcoholic fatty liver disease.
Type 2 diabetes, or non insulin-dependent diabetes mellitus (NIDDM), is characterized by the fact that patient produce insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while at the same time demonstrating hyperglycemia. Type 2 diabetics often develop “insulin resistance”, such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissues, is diminished and those patients are thus at increased risk of cardiovascular complications, e.g. atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy.
Many patients who have insulin resistance, but have not developed type 2 diabetes, are also at a risk of developing symptoms referred to as Metabolic Syndrome. Metabolic syndrome is characterized by insulin resistance, along with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL and high VLDL. These patients, whether or not they develop overt diabetes mellitus, are at increased risk of developing cardiovascular complications.
Furthermore epidemiologic evidences suggest that obesity increases the risk of cirrhosis. For example, in autopsy series, obesity was identified as the only risk factor for disease in 12% of cirrhotic subjects (Yang, S. Q. et al.; 1997). Notably, cirrhosis is approximately six times more prevalent in obese individuals than in the general population. The degree of obesity correlates positively with the prevalence and severity of fatty liver (steatosis), and this in turn correlates with steatohepatitis.
Thus, there is a need for treating obesity and obesity-related disorders, such as NIDDM, metabolic syndrome or non-alcoholic fatty liver disease.
Weight loss drugs that are currently used for the treatment of obesity have limited efficacy and significant side effects. Studies of the weight loss medications orlistat (Davidson M H. et al. 1999), dexfenfluramine (Guy-Grand, B. et al. 1989), sibutramine (Bray, G. A. et al. 1999) and phentermine (Douglas, A. et al. 1983) have demonstrated a limited weight loss of about 5%-10% of body weight for drug compared to placebo. However the side effects of these drugs limit their use. For instance dexfenfluramine was withdrawn from the market because of suspected heart valvulopathy; orlistat is limited by gastrointestinal side effects; the use of topiramate is limited by central nervous system effects; and the use of sibutramine is limited by its cardiovascular side effects which have led to reports of deaths and its withdrawal from the market in Italy.
Recent studies suggest that antagonists of the cannabinoid receptor type 1 (CB1) may be useful for the treatment of obesity and obesity-related disorders. For example, the international patent publication WO2005/046689 discloses CB1 antagonists derived from pyrazole for the treatment or prevention of obesity and obesity related disorders. More specifically, Rimonabant (SR 141716), which is a selective cannabinoid CB1 receptor antagonist, has undergone extensive testing in the treatment of obesity. In 4 clinical studies with more than 6000 overweight and obese patients (Rimonabant in Obesity (RIO) program), rimonabant has demonstrated consistent efficacy with regard to weight loss and reduction of the associated cardiometabolic risks (Van Gaal L F. et al. 2005; Després J P. et al. 2005; Pi-Sunyer F X. et al. 2006).
On the contrary, the only studies available on that subject, performed with antagonists of the cannabinoid receptor type 2 (CB2) ruled out that they may show beneficial effect on obesity and obesity-related disorders based on their absence of effect on food intake or locomotor activity (Wiley J L et al. 2005; Williams C M. et al. 2002).
The international patent application WO 98/31227 previously described pyrazole derivatives which are said to be modulators (antagonist or agonist) of CB2 receptor. The disclosed modulators were suggested to be useful for the treatment of immunologically mediated inflammatory diseases, including diabetes. However, it was not specified whether an antagonist or agonist of CB2 receptor should be used for that treatment and the proposed application was purely speculative.
The international patent application WO 2006/105217 further suggested that CB2 receptor inhibitors are expected to have therapeutical utility in the control of diabetes, cerebral stroke and cerebral ischemia. However, these therapeutical applications were also purely speculative.
The instant application formally demonstrates that CB2 receptor plays a major role in the development of obesity, insulin resistance, inflammation and hepatic steatosis. Hence, a new pathway for the treatment and/or the prevention of obesity and obesity-related disorders is provided which involves interfering with CB2 receptor expression and/or activity.